LY6E impairs coronavirus fusion and confers immune control of viral disease

Abstract

Zoonotic coronaviruses (CoVs) are significant threats to global health, as exemplified by the recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 . Host immune responses to CoV are complex and regulated in part through antiviral interferons.However, the interferon-stimulated gene products that inhibit CoV are not well characterized 2 . Here, we show that interferon-inducible lymphocyte antigen 6 complex, locus E (LY6E) potently restricts cellular infection by multiple CoVs, including SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV). Mechanistic studies revealed that LY6Einhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in hematopoietic cells were highly susceptible to murine CoV infection. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic and splenic immune cells and reduction in global antiviral gene pathways. Accordingly, we found that Ly6e directly protects primary B cells and dendritic cells from murine CoV infection. Our results demonstrate that LY6E is a critical antiviral immune effector that controlsCoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo, knowledge that could help inform strategies to combat infection by emerging CoV. author/funder. All rights reserved. No reuse allowed without permission.

A single-cell RNA expression map of human coronavirus entry factors

“…Additionally, FURIN is known to activate MERS-CoV and possibly SARS-CoV-2 (Mille and Whittaker, 2014;Walls et al, 2020) and Cathepsins (CTSL/B) can also substitute for TMPRSS2 to prime SARS-CoV (Simmons et al, 2013b). Importantly, we also enlisted several restriction factors that are known to protect cells against entry of SARS-CoV-2 (LY6E) (Pfaender et al, 2020) or a broad range of enveloped RNA viruses, including SARS-CoV (IFITM1-3) (Huang et al, 2011). We also considered a few additional factors that act postentry, but relatively early in viral replication such as TOP3B and MADP1 (ZCRB1), which may expressed in a tissue/cell type-specific fashion and are known to be essential for genome replication of SARS-CoV-2 and SARS-CoV, respectively (Prasanth et al, 2020;Tan et al, 2012).…”

“…It is made available under a The copyright holder for this preprint (which this version posted May 17, 2020. . https://doi.org/10.1101/2020.05.08.084806 doi: bioRxiv preprint 6 SARS-CoV-2, such as LY6E (Pfaender et al, 2020) and IFITM proteins (Huang et al, 2011). Overall, our understanding of cellular factors underlying the potential tropism of SARS-CoV-2 remain very partial.…”

Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies

“…A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option, whereas the sera from convalescent SARS patients crossneutralized SARS-2-S-driven entry [17]. Interferon-inducible lymphocyte antigen 6 complex, locus E (LY6E) inhibits SARS-CoV-2 entry into cells in vitro and in vivo by interfering with spike protein-mediated membrane fusion [51]. Potential therapeutic targets for SARS-CoV-2 were analyzed, and inhibitors of 3-chymotrypsin-like protease, spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were screened [52].…”

Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer

“…Figure S3b generated with their data shows that AT2 and ciliated cells originated from PNECs in this model have lost Ascl1 but increased Yap1 expression. Ly6e and Tmprss2, genes involved in coronavirus defense (42) and hijacked entry (43) respectively, were also upregulated.…”